2-thioxo-1h-1,4-benzodiazepine-1-acetic acid alkyl esters

ABSTRACT

Novel 7-substituted-3,5-dihydro-as-triazino(4,3-a) (1,4)benzodiazepin-2(1H)-ones, 7-substituted-3,5-dihydro-astriazino(4,3-a) (1,4)benzodiazepine-2(1H)-thiones, the 6-oxide derivatives thereof, the intermediate 5-substituted-2,3-dihydro2-thioxo-1H-1,4-benzodiazepine-1-acetic acid alkyl esters, pharmacologically acceptable acid addition salts thereof, and processes for the production thereof. The compounds of this invention and the pharmacologically acceptable acid addition salts thereof are central nervous system depressants which are useful as sedatives, hypnotics, tranquilizers, muscle relaxants and anticonvulsants. They are also useful as feed additives for increasing growth rate and feed efficiency of livestock and poultry, milk production in mammals and egg production in birds.

United States Patent [191 Szmuskovicz [451 Aug. 26, 1975 [75] inventor: Jacob Szmuskovicz, Kalamazoo,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Nov. 5, 1973 [2]] Appl. No.: 412,551

Related US. Application Data [62] Division of Ser. No. 215,] 18, .Ian. 3, 1972, Pat. No.

Primary Examiner-Henry R. .liles Assistant Examiner-Robert T. Bond Attorney, Agent, or Firm-Ward F. Nixon; John T. Reynolds [57] ABSTRACT Novel 7-substituted-3,S-dihydro-as-triazino[4,3-a]- l ,4]benzodiazepin-2( lH)-ones, 7-substituted-3,5- dihydro-as-triazino[4,3-a][ l,4]benzodiazepine-2( l H thiones, the 6-oxide derivatives thereof, the intermediate S-substituted-Z,3-dihydro-2-thioxo-l H- l ,4- benzodiazepine-l-acetic acid alkyl esters, pharmacologically acceptable acid addition salts thereof, and processes for the production thereof. The compounds of this invention and the pharmacologically acceptable acid addition salts thereof are central nervous system depressants which are useful as sedatives, hypnotics, tranquilizers, muscle relaxants and anticonvulsants. They are also useful as feed additives for increasing growth rate and feed efficiency of livestock and poultry, milk production in mammals and egg production in birds.

4 Claims, No Drawings Z-THIOXO-lH-l ,4-BENZODlAZEPlNE-l -ACETIC ACID ALKYL ESTERS This is a division. of application Ser. No. 2l5,l l8. 5 filed Jan. 3. 1972. now US. Pat. No. 3.818.003. issued June 18. 1974.

SUMMARY OF THE INVENTION The novel 7-substituted-3,S-dihydro-astriazinol4.3- a][l.4]benzodiazepines of this invention and the 6- oxide derivatives thereof are illustratively represented by the generic formulae I and ll. respectively. and the novel intermediate 5-substituted-2.3-dihydro-2-thioxolH-l .4-benzodiazepine-l-acetic acid alkyl esters by generic formula III as follows:

R CDOR R lll wherein R. R, and R are each selected from the group consisting of hydrogen and alkyl of l to 3 carbon atoms. inclusive; R is selected from the group consisting of hydrogen. alkyl of 1 to 3 carbon atoms. inclusive. hydroxy, acetoxy and propionyloxy; R and R are each selected from the group consisting of hydrogen. alkyl of l to 3 carbon atoms. inclusive. halogen. nitro. cyano. amino, trifluoromcthyl, alkoxy, alkylthio. alkylsulfinyl. alkylsulfonyl. alkanoylamino and dialkylamino in which the carbon chain moieties are of l to 3 carbon atoms, inclusive; R is selected from the group consisting of pyridyl. Z-pyrimidinyl. fury]. pyrrolyl. thienyl, cycloalkyl of 5 to 7 carbon atoms. inclusive. and a phenyl radical of the formula in which R and R each have the same meanings as given above for R, and R R is alkyl of l to 3 carbon atoms, inclusive, and Z is selected from the group consisting of oxygen and sulfur.

In this application alkyl is exemplified by methyl. ethyl, propyl and isopropyl. Halogen is exemplified by fluoro, chloro. and bromo. Alkoxy is exemplified by methoxy. ethoxy. propoxy and isopropoxy. Alkylthio is exemplified by methylthio. ethylthio, propylthio and isopropylthio. Alkylsulfinyl is exemplified by methylsulfinyl. ethylsulfiny], propylsulfinyl and isopropylsulfinyl. Alkylsulfonyl is exemplified by methylsulfonyl. ethylsulfonyl. propylsulfonyl and isopropylsulfonyl. Alkanoylamino is exemplified by formylamino. acetylamino and propionylamino. Dialkylarnino is exemplified by dimethylamino. diethylamino. methylethylamino. methylpropylamino, ethylpropylamino. dipropylamino. diisopropylamino and the like. Cycloalkyl is exemplified by cyclopentyl. cyclohexyl and cycloheptyl. Cycloalkenyl is exemplified by lcyclopentenyl, l-cyclohexenyl. l-cycloheptenyl. 2- cyclopentenyl. 2-cyclohexenyl, 2-cycloheptenyl. 3- cyclopentenyl. 3-cyclohexenyl, 3-cycloheptenyl and 4-cycloheptenyl.

The novel compounds of this invention represented by formulae I. ll and ill. above. exist in either the nonprotonated (free base) form or in the protonated (acid addition salt) form. depending on the pH of the environment. They form stable protonates. i.e.. pharmacologically acceptable acid addition salts. on acidification of the free base with suitable pharmacologically acceptable acids. for example. hydrochloric. hydrobromic. sulfuric. phosphoric. nitric, acetic. propionic. palmitic, benzoic. salicylic, hexynoic. phenylbutyric. naphthoic. glycolic. suceinic. nicotinic. tartaric, maleie. malic. pamoic. methanesulfonic. cyclohexanesulfonic. citric. and lactic acids. and the like. Conversely. the free bases of the novel compounds of formulae l. [I and Ill can be obtained from salts. (e.g.. from the hydrochloride or sulfate salt) by neutralization with a base such as sodium hydroxide. extracting with a waterimmiscible solvent, for example chloroform. drying the extract, for example with anhydrous sodium sulfate. and removing the solvent by evaporation.

The novel compounds offormulae I. II and Ill and the pharmacologically acceptable acid addition salts thereof have sedative. hypnotic. anticonvulsant. tranquilizing and muscle relaxant effects in mammals and birds. and are useful as feed additives for increasing the growth rate and feed efficiency of livestock and poul 3 try, milk production during lactation in mammalian species and egg production in avian species.

Sedative effects of the compounds of this invention 4 The following compounds typical of this invention have (by intraperitoneal injection) ED. as shown in the table below.

ED in mgjkg. COMPOUND CH D P Ni Str 9-chloro-3.5-dihydro-7-phenyl-as-triazinol4.3- all l.4]benzodiaZcpin-2( lHl-onc l0.0 23.0 23.0 9.0 l0.0 40.0 9-chloro-7-(o-chlorophenyl )3.5dihydrn-as triazino[4.3-all l.4]bcnzodiazepin-2( lH )-one 0.2 0.036 0.01 0.04 0.045 0.6 )-chloro-7-( o-chlorophenyl )-3 .S-dihydro-3- mcthyl-as-triazinol4.3-all l.4]henzodiazcpin- 2l lH )'one 0.9 0.09 0.22 0.06 0.07 3.2 7-(o-chlorophenyl)-3.5-dihydru-as-triazinol4.3- all 1 .4 Ibenzodiazepin-2( lH l-one 10.0 0.7 2.8 0.9 0.9 l 12 7-(o-chlorophenyl)3.5-dihydro-3-methylastriazino[4.3-a l ,4]henzodiazepin-2( lHJ-one 28.0 4.0 6.0 4.0 4.5 100 9-ehloro-3.5-r.lihydro-3-methyl-7phenyl-astriazino[4.3-a]l l.4]benzodiazepin-2l lH)one 9.0 2.5 4.5 1.6 1.6 7-chloro-2.3-dihydro-S-phenyl-Z-thioxol H-] .4- henzodiazepine-Lacetic acid methyl ester 25.0 23.0 36.0 20.0 20.0 50 7-chloro-5-(u-ch|orophenyl)-2.3-dihydro-2-thioxolH-l .4-benzodiazepine-l-acetic acid methyl ester ll.0 25.0 79.0 25.0 29.0 5-(o-ehlorophenyl)-2.3-dihydro-2-thioxo-l H-1 .4- hernzodiazepine-l-acetic acid methyl ester 36.0 9.0 63.0 79.0 56.0

Ch chimney test I) dish test P pedestal test Ni nicotine antagonism l2). (3| test Str strychnine antagonism test were determined by the following tests in mice:

The pharmaceutical forms contemplated by this in- Chimney test: [Med Exp 4 145 (96in The test 35 vention include pharmaceutical compositions suited determines the ability ofmice to back up and out of a vertical glass cylinder within 30 seconds. At the effective dosage, 50% of the tranquilized mice failed to do so.

Dish test: Untreated (control) mice in Petri dishes (10 cm. diameter, 5 cm. high. partially embedded in wood shavings). climb out in a very short time. Tranquilized mice remain in the dish for more than 3 minutes. ED equals the dose of test compound at which 50% of the mice remain in the dish.

Pedestal test: The untreated mouse leaves a standard pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice stay on the pedestal for more than 1 minute.

Nicotine antagonism test: Mice in a group of 6 are injected with the test compound. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show over-stimulation. i.e.. (I) running convulsions followed by (2) tonic extensor fits; followed by (3) death.

for oral. parenteral and rectal use. e.g.. tablets, powder packets. cachets. dragecs. capsules. solutions. suspensions. sterile injectable forms. suppositories, bougics. and the like. For oral administration suitable diluents or carriers such as lactose. proteins. lipids. calcium phosphate. cornstarch. stearic acid. methylcellulose. and the like can be used as carriers or for coating purposes. 0ils. such as coconut oil. sesame oil. safflower oil. cottonseed oil. and peanut oil can be used for preparing solutions or suspensions of the active drug. sweetening. coloring. and flavoring agents can be added.

Food premixcs with starch. oatmeal. dried fishmeat. fishmeal. flour and the like can be prepared and incorporated into an animal feed for mammals and birds.

As feed additives the compounds of formulae I. ll and Ill can be used in dosages of 0.003 mg. to 50 mg./animal/day in a feed to increase growth. feed consumption and feed efficiency in livestock and poultry, milk production in mammals and egg production in birds.

As tranquilizers the compounds of Formulae I, ll and Ill can be used in dosages of 0.0l mg. to 20.0 mg./kg. in oral or injectable preparations as described above. to alleviate tension and anxiety in mammals. or birds. such as occurs when animals are being transported.

DETAILED DESCRIPTlON OF THE lNVENTlON The novel compounds of this invention and processes for their production are illustratively represented by the following sequence of formulae:

cooas 0 Rs R Step 2 and 2a l 2 Step 4 wherein R. R, R R R R R and Z have the meanwherein R R R and R have the meanings previously ings previously given. given, with an alkyl 2-haloalkanoate of the formula The starting compounds of formula IV are for the most part known; for example. their preparation is disclosed in Belgium Pat. No. 64/2839 published Dec. 23, 1964. They are prepared by reacting the sodium salt of 60 R a compound of the formula: l

Y-C-COOR. vn

l H R R as N wherein R. R and R have the meanings previously Vl given and Y is selected from the group consisting of R chlorine. bromine and iodine. The reaction is conducted in an organic solvent medium such as methanol. ethanol. propanol, dimethylformamide, benzene. toluene, mixtures thereof and the like. Temperature and pressure are not critical; the reaction can be carriedout at room temperature or at elevated temperatures. at atmospheric pressure or at elevated or reduced pressures. A temperature of from about 50 C. to about 125 C. and atmospheric pressure are generally pre ferrcd.

The process of this invention comprises the following steps:

1. A 2.3-dihydro-2-oxo-l H-l ,4-benzodiazepine-1- acetic acid alkyl ester (IV) is heated with phosphorus pentasulfide in a solvent such as pyridine, benzene. toluene or xylene at between about 80 to about I40 C. for between about 30 minutes to about 24 hours in accordance with the procedure disclosed by Archer et al., J. Org. Chem. 29. 231 (1964) and US. Pat. No. 3,422,091. The 2.3-dihydro-2-thioxol H-l ,4-benzodiazepinel -acetic acid alkyl esters of formula V thus obtained are recovered from the reaction mixture and purified by conventional methods. for example by chromatography on silica gel and/or crystallization from a suitable organic solvent such as an alkanol, e.g.. methanol, ethanol, 1- propanol, 2-propanol and the like, methylene chloride, chloroform, ethyl acetate, mixtures thereof and the like.

2. The 2,3-dihydro-2-thioxo-lH-l .4-benzodiazepinel-acetic acid alkyl ester (V) thus obtained is reacted with a hydrazine of the formula:

R NH-NH vm wherein R has the meaning previously given to produce a compound of formula la. in carrying out the reaction compound V. is heated to between about 60 to 140 C. (preferably at reflux temperature) with one molar equivalent of the desired hydrazine of formula Vlll in an organic solvent, preferably a lower alkanol, e.g.. methanol, ethanol, l-propanol, 2-propanol, lbutanol, 2-butanol, dioxane and the like. The reaction period is between about I to about 48 hours. At the termination of the reaction, the resulting 3,5-dihydro-astriazino[4,3-a][1,4]benzodiazepin-2(lH)-one (la) is isolated from the reaction mixture by conventional methods, for example. by crystallization directly from the reaction mixture, followed by recrystallization from a suitable organic solvent such as a lower alkanol, chloroform. ether, ethyl acetate, methylene chloride and the like or mixtures thereof such as methanolchloroform and the like; or by gradient elution chromatography from an absorbent column, e.g., silica gel. with a suitable solvent such as acetone, ethyl acetate. ether. methylene chloride, cyclohexane. Skellysolve B. hexane. a lower alkanol, mixtures thereof such as methanol-ethyl acetate. ethyl acetatecyclohcxane and the like.

20. Alternatively. compounds of formula la wherein R is alkyl are prepared by alkylating a compound of formula la wherein R in hydrogen. The latter compound is converted to the sodium or potassium salt with sodium hydride or potassium hydride and the salt is treated with an alkyl halide of the formula:

R.,-Y Ix wherein R is alkyl as hereinbefore defined and Y is halogen as hereinbefore defined. The reaction is preferably carried out in an in ert organic solvent such as dimethylformamide and at a temperature within the range of from about 50 to I40 C. The product is recovered from the reaction mixture by conventional methods, for example the solvent is removed by evaporation, water is added and the product is recovered by filtration or extraction with a waterimmicible organic solvent.

3. The 3.5-dihydro-as-triazinol4,3- a][ l.4]benzodiazepin-2( lH)-thiones of formula lb are prepared by treatment of the corresponding compounds of formula la with phosphorus pentasulfide in accordance with the precedures disclosed in step 1 above.

The 3,S-dihydro-as-triazino[4.3- a][ l,4]benzodiazepin-2( l H)-ones (la) and the 3,5- dihydro-as-triazinol4,3-a}- [l,4]benzodiazepin-2(lH)-thiones (lb) are converted to the corresponding 6-oxides (II) by reacting them with a peracid such as peracetic acid. perphthalic acid, perbenzoic acid, m-chloroperbenzoic, acid and the like. The reaction is conducted in a suitable organic solvent such as a lower alkanol, e.g.. methanol. ethanol. 1- propanol, 2-propanol and Z-butanol; chloroform, methylene chloride and the like at a temperature within the range of from about 0 C. to about 25 C. for a period of from about 6 to 48 hours. The resulting 6-oxides (ll) are recovered from the reaction medium and purified by conventional methods such as chromatography and/or crystallization.

The following Preparations and Examples are illustrative of the products and processes of the present invention but are not to be construed as limiting.

PREPARATlON l 7chloro-2,3-dihydro-2-oxo-5 -phenyll H- l,4-benzodiazepine-l-acetic acid methyl ester (IV) Sodium methoxide (5.95 g.. 0.ll mole) is added to a solution of 7-chloro-l,3-dihydro-5-phenyl-2H-l ,4- benzodiazepin-Z-one (VI) (27 g., 0.1 mole) in 200 ml. of dimethylformamide and the mixture is stirred and heated on a steam bath for about 20 minutes. To this mixture is added a solution of methyl bromoacetate (Vll) l6.7 g., 0.ll mole) in ml. of toluene during 1 hour while stirring and heating are continued. The mixture is heated for an additional 2 hours, allowed to stand overnight at room temperature (abut 25 C.) and evaporated to dryness in vacuo. The residue is stirred with 500 ml. of water until a suspension results. The suspension is filtered and the solid thus obtained is crystallized first from ether and then from methanol to give 14.5 g. (42% yield) of 7-chloro-2,3-dihydro- Z-oxo-S-phenyl-l H-l .4-benzodiazepinel -acetic acid methyl ester (IV); m.p. l37-l38 C.; ultra-violet, infrarcd, NMR and mass spec. are in accordance with the structure.

PREPARATION 2 7-chloro-S-(o-chlorophenyl )2.3-dihydro- 2-oxol H-l .4-benzodiazepine-l-aeetic acid methyl ester IV) Sodium methoxide (5.95 g., 0.l l mole) is added to a solution of 7-chloro-l.3-dihydr0-5-lo-chlorophenyl)- 2H-l.4-benzodiazepin-2one (VI) (30.5 g.. 0.1 mole) in 200 ml. of dimethylformamide and the mixture is heated at 95 for about minutes. To the mixture is added a solution of methyl bromoacetate (V11) (16.7 g., 0.11 mole) in 165 ml. of toluene during 55 minutes while heating is continued. After heating the mixture for an additional 6.25 hours it is evaporated to dryness, and the residue is stirred with 400 ml. of water and 200 ml. of ether. The resulting suspension is filtered and the solid thus obtained is crystallized from methylene chloride-methanol to give 24.9 g. of 7-chloro-5-(ochlorophenyl)-2,3-dihydro-2-oxo-lH-1.4- benzodiazepine-I-acetic acid methyl ester (IV); m.p. l93194 C.

Anal. Calcd. for C H CI N O C, 57.31; H. 3.74; CI, 18.80; N. 7.43. Found: C. 57.38; H. 4.03;Cl, 18.92; N. 7.55.

PREPARATION 3 5-(o-chlorophenyl)-2.3 dihydro-2-oxo-lH- l.4-benzodiazepine-l-acetic acid methyl ester (IV) Sodium methoxide (2.26 g.; 0.042 mole) is added to a solution of S-(o-chlorophenyl)-l.3-dihydro-2H1,4- benzodiazepin-2-one (VI) (10.3 g., 0.038 mole) in 100 ml. ofdimethylformamide and the mixture is heated at 95 for about 25 minutes. To the mixture is added a solution of methyl bromoacetate (VII) (6.4 g., 0.042 mole) in 65 ml. of toluene during 45 minutes while heating is continued. The mixture is heated for an additional 5.5 hours and allowed to stand overnight. It is evaporated to dryness and the residue is stirred with a mixture of 150 ml. of water and 150 ml. of ether. The resulting suspension is filtered and the solid thus obtained is crystallized from methanol to give 7.9 g. of 5- (o-chlorophcnyl )-2.3-dihydro-2-oxol H-1 .4- benzodiazepinel-acetie acid methyl ester (IV); m.p. 166-l67.5 C.

Anal. Calcd. for C,,.H, CIN O,,: C. 63.07; H. 4.4 l Cl. 10.34; N. 8.17. Found: C. 62.87; H. 4.44; CI. 10.38;. N. 8.17.

PREPARATION 4 7-ehloro-2.3-dihydro-a-mcthyl-2-oxo-5-(2.6- difluorophenyl )-l Hl .4-benzodiazepinel -acetic acid methyl ester (IV) A mixture of 0.1 mole of 7-chloro-1.3-dihydro-5- (2.6-difluorophenyl )-2H-l .4-benzodiazepin-2-one (VI) and 0.11 mole of sodium methoxide in about 200 ml. of tetrahydrofuran is heated at about 95 C. for about minutes. To the mixture is added a solution of 0.1 1 mole of methyl 2-bromopropionate (VII) in about 200 ml. of toluene over a period of about 1 hour at about 95 C.. and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether. methanol. methylene chloride. methylene chloridemethanol and the like to obtain 7-chloro-2.B-dihydro-amethyl-2-oxo 5 (2.6-difluorophenyl)-lH-l.4 benzodiazepine-l-acetic acid methyl ester (IV).

PREPARATION 5 7-trifluoromethyl-2.3-dihydro-Z-oxo-S-phenyll H-1 .4- benzodiazepine-l-aeetie acid ethyl ester (IV) A mixture of 0.1 mole of 7-trifluoromethyl-l ,3- dihydro-5-phenyl-2H- l .4-benzodiazepin-2-one (V1) and 0.1 1 mole of sodium methoxide in about 200 ml. of tetrahydrofuran is heated at about C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of ethyl bromoacetate (VII) in about 200 ml. of toluene over a period of about 1 hour at about 95 C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether. methanol. methylene chloride, methylene chloride-methanol and the like to obtain 7-trifluoromethyl-2.3-dihydro-2-oxo- S-phenyll H-] ,4-benzodiazepin-1-acetie acid ethyl ester (IV).

PREPARATION 6 7-chloro-2,3-dihydro-a.a-dimethyI-2-oxo-5-phenyllH-l .4-benzodiazepine-1-acetic acid methyl ester (IV) A mixture of 0.1 mole of 7-chloro-l,3-dihydro-5- phenyl-2H-1,4-benzodiazepin-2-one (VI) and 0.11 mole of sodium methoxide in about 200 ml. oftetrahydrofuran is heated at about 95 C. for about 20 minutes. To the mixture is added a solution of 0.1 1 mole of methyl 2-bromo-2-methylpropionate (VII) in about 200 ml. of toluene over a period of about 1 hour at about 95 C.. and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether. methanol, methylene chloride, methylene chloridemethanol and the like to obtain 7-chloro-2.3-dihydroa.adimethyLZ-oxo-S-phenyl-1H-l .4-benzodiazepinel-acetic acid methyl ester (IV).

PREPARATION 7 7-chloro-a-ethyl-2,3-dihydro-a-methyl-Z-oxo-S-(ochlorophenyl 1 11-1 ,4-benzodiazepinel -acetic acid propyl ester (IV) A mixture of 0.1 mole of 7-chloro-l .3-dihydro-5-(ochlorophenyl )-2H- 1 .4-benzodiazepin-2-one (VI) and 0.11 mole ofsodium methoxide in about 200 ml. oftetrahydrofuran is heated at about 95 C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of propyl 2-bromo-2-methylbutyrate (VII) in about 200 ml. of toluene over a period of about 1 hour at about 95 C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol. methylene chloride. methylene chloridemethanol and the like to obtain 7-chloro-a-ethyl-2.3- dihydro-a-methyl-2-oxo-5-(o-chlorophenyl)- l H-1 .4- benzodiazepine-l-acetic acid propyl ester (IV).

PREPARATION 8 7-bromo2.3-dihydro-Z-oxo-a-propyl-S -(2-pyridyl )-l H- l .4 benzodia2epinel -acetic acid methyl ester (IV) A mixture of 0.1 mole of 7-bromo-l,3-dihydro-5-(2- pyridyl)-2H-l.4-benzodiazepin-2-one (VI) and 0.1 l mole of sodium methoxidc in about 200 ml. of tetrahydrofuran is heated at about 95 C. for about 20 minutes. To the mixture is added a solution of 0.1 1 mole of methyl Z-bromovalerate (VII) in about 200 ml. of toluene over a period of about 1 hour at about 95 C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether. methanol. methylene chloride, methylene chloride-methanol and the like to obtain 7-bromo-2,3-dihydro-Z-oxo-apropyl-(2-pyridyl)-1H-1,4-benzodiazepine-l-acetic acid methyl ester (IV).

PREPARATION 9 7-chloro-5-cyclohexyl-2.3-dihydro-a-isopropyl-2-oxolH-l .4-benzodiazepine l-acetic acid methyl ester (IV) A mixture of 0.1 mole of 7-chloro-1.3-dihydro-5 cyclohexyl-ZH-l,4-benzodiazepin-2-one (VI) and 0.11 mole of sodium methoxide in about 200 ml. oltetrahydrofuran is heated at about 95 C. for about minutes. To the mixture is added a solution of 0.1 l mole of methyl 2-bromo-3-mcthylbutyrate (VII) in about 200 ml. of toluene over a period of about I hour at about 95 C.. and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether. methanol. methylene chloride. methylene chloride-methanol and the like to obtain 7-chloro-5-eyclohexyl-2.3-dihydro-aisopropyl-Z-oxol H-l .4-benzodiazepinel -acetic acid methyl ester (IV).

In the manner given in Preparations 1-9 above. other l.3-dihydro-2H-1.4 benzodiazepin-2-ones of formula VI can be reacted with the appropriate alkyl 2- haloalkanoate of formula VII to obtain other 2.3- dihydro-Z-oxol H- l .4-benzodiazepinel -acetic acid alkyl esters of formula IV. For example. the following 1.3-dihydro-2H- l ,4-benzodiazepin-2-ones:

7-bromo-1.3-dihydro-5-phenyl-2H-l .4- benzodiazepin-Z-one;

7-f1uoro-l ,3-dihydro-5-phenyl-2H-l .4- benzodiazepin-Z-onc;

l.3-dihydro-7-nitro-5-phenyl-2H'l .4-benzodiazepin- 2-one:

7-cyano-l ,S-dihydro-S-phenyl-ZH-l .4- benzodiazepin-2-one;

7-bromo-5-(o-chlorophenyl )-l .3-dihydro-2H- l .4- benzodiazcpin-Z-one;

5-( o-chlorophenyl )-7-fluoro-l .3-dihydro-2H-l .4- benzodiazepin-Z-onc;

5-( o-chlorophenyl )-l .3-dihydro-7-nitro-2H-l .4- benzodiazepin-Z-one;

S-(o-chlorophenyl )-l .3-dihydro-7-( trifluoromethyl ZH-l .4-benzodiazepin-2-one;

5-( o-chlorophenyl )-7-cyanol .3-dihydro-2H-l ,4- benzodiazepin-Z-one;

5-( o-chlorophenyl )-l ,3-dihydro-7-( methylthio )-2H- l.4-bcnzodiazepin-Z-one:

7-chloro-5-( o-l'luorophenyl )-l .3-dihydro-2H- l .4- benzodiazepinQ-one;

7-bromo-5-(o-fluorophenyl )-l .3-dihydro-2H-l .4- benzodiazepin2-one;

5-(o-I'luorophcnyl)-1.3-dihydro-7-nitro-2H-l ,4- benzodiazepin-2-one;

5-(o-fluorophenyl)- l .3-dihydro-7(trifluoromethyl 2H-1.4-benzodiazepin-2-one;

7-cyano-5-(o-fluorophenyl )-1 .3-dihydro-2H-1 .4- benzodiazepin-2-one;

5-(o-fluorophenyl)-1.3-dihydro-7-(methylthio)-2H- 1.4-benzodiazepin-2-one;

7-chloro-l .3dihydro-5-( 2-pyrimidinyl )-2H- 1 ,4- benzodiazepin-Z-one;

7-bromo-5'(2-furyl)-l .3-dihydro-2H-l .4- benzodiazepin-Z-one;

1.3-dihydro-7-nitro-5-( Z-thienyl )-2H-] .4- benzodiazepin-Z-one;

S-cyclohexyl-l .3-dihydro-7-(trifluoromethyl)-2H- 1,4-benzodiazepin-2-one;

7-cyano-5-( l-cyclohexenyl)-1.3-dihydro-2H-L4- benzodiazepin-Z-one and the like can be reacted with a 2-haloalkanoate (VII). for example. methyl bromoacetate. to obtain:

7 bromo-2.3-dihydro-2-oxo-5-phenyll H-l .4- benzodiazepine-l-acetic acid methyl ester;

7-fluoro-2.3-dihydro-2-oxo-5-phenyll H-l .4- benzodiazepine-l-acetic acid methyl ester;

2,3-dihydro-7-nitro2-oxo-5-phenyl-1H-l .4- benzodiazepine-l-acetic acid methyl ester;

7-cyano-2.3-dihydro2-oxo-5-phenyl-1H-l.4- benzodiazepine-l-acetic acid methyl ester;

2,3-dihydro-7-(methylthio)-2-oxo-5-phenyl1H-l .4- benzodiazepine-l-acetic acid methyl ester;

7-bromo-5-(o-chlorophenyl )-2.3-dihydro-2-oxol H- 1,4-benzodiazepine-l-acetic acid methyl ester;

5-(o-chlorophenyl)-7-fluoro2,3-dihydro-2-oxo-1H- 1,4-benzodiazepine-l-acetic acid methyl ester;

S-(o-chlorophenyl )-2.3-dihydro-7-nitro-2-oxol H- l.4-benzodiazepine-l-acetic acid methyl ester;

5-(o-chlorophenyl)-2.3-dihydro-2-oxo-7- (trif'luoromethyl l H- l .4-benzodiazepine- 1 -acetic acid methyl ester;

S-(o-chlorophenyl )-7-cyano-2.3-dihydro-2-oxol H- l.4-benzodiazepine-l-acetic acid methyl ester;

5-(o-chlorophenyl)-2.3-dihydro-7-(methylthio)-2 oxo-l H-l .4-benzodiazepine-l-acetic acid methyl ester;

7-chloro-2,3-dihydro-2-oxo-S-(Z-pyrimidinyl)-lH- l.4-benzodiazepine-l-acetic acid methyl ester;

7-bromo-5-( 2-furyl )-2.3-dihydro-2-oxo- 1 H4 .4- benzodiazepine-l-aeetic acid methyl ester;

7-fluoro-2.3-dihydro-2 oxo-5-(2-pyrrolyl)1H-1,4- benzodiazepine-Lacetic acid methyl ester;

2.3-dihydro-7-nitro-2-oxo-5-(2-thienyl)-lH-l.4- benzodiazepine-l-acctic acid methyl ester;

S-cyclohexyl-Z.3-dihydro-2-oxo-7-(trifluoromethy1)- lH-1.4-benzodiazepine-1-acetic acid methyl ester;

7cyano-5( l-cyclohexeny1)-2.3-dihydro-2-oxo-lH- 1.4-benzodiazepine-l-acetic acid methyl ester; respectively; and the like.

Similarly other alkyl Z-haloalkanoatcs offormula VlI such as:

ethyl chloroacetate propyl bromoacetate isopropyl iodoacetate methyl 2-bromopropionate methyl 2-chlorobutyrate ethyl 2-iodovalerate propyl 2-bromo-3-methylbutyrate methyl 2-bromo-2-methylpropionate propyl 2-bromo-2-ethylbutyrate methyl 2-chloro-2-methylbutyrate ethyl 2-bromo-2-cthylva1erate and the like. can be substituted in place of methyl bromoacetate to obtain the corresponding 2.3-dihydro- 2-oxo-lH-1.4-benzodiazcpin-l-acetic acid alkyl ester of formula IV.

EXAMPLE 1 7-chloro-2.3-dihydro-5-phcnyl-2-thioxo-1H- 1.4-ben7.odiazepine-lacetic acid methyl ester (V) A mixture of 6.35 g. (0.0186 mole) of 7-chloro-2.3- dihydro-2-oxo-5-phenyll H- l ,4-benzodiazepinel acetic acid methyl ester (1V). 4.42 g. (0.0199 mole) of phosphorus pentasulfidc and 185 ml. of pyridine is heated under reflux for about 19 hours. The pyridine is evaporated. 100 ml. of cold water is added. and the product is extracted with four 100-m1. portions of methylene chloride. The extracts are combined. washed with sodium bicarbonate solution and with saturated salt solution. dried over magnesium sulfate and evaporated to give 2.4 g. of residue. The residue thus obtained is extracted with eight 250-ml. portions of boiling ether. The extracts are combined and concentrated. On standing 2.1 g. of 7-ch1oro-2.3-dihydro-5- phenyl-2-thioxo-1 H-l .4-bcnzodiazepin-1 -acetic acid methyl ester (V). m.p. 180-182 C. crystallizes from solution; recrystallization from ether raises the melting point to l85-l87 C.

EXAMPLE 2 7-chloro 2.3-dihydro-5-pheny1-2 -thioxo1H-l .4-bcnzodiazepinel-acetic acid methyl ester (V) The procedure of EXAMPLE 1 is repeated to the point where a residue is obtained following evaporation of the methylene chloride. The residue is thus obtained is chromatographed on silica gel using 50% ethyl acetate-cyclohcxane to give 7-chloro-2.3-dihydro-5- phenyl-2-thioxo-1H-l.4-benzodiazepinc-l-acetic acid methyl ester (V). m.p. 188-189 C. (from ether).

Anal. Calcd. for c,,.H. .,c|N o. ,s; C. 60.24; H. 4.21; Cl. 9.88; N. 7.81: S. 8.94. Found: C. 60.14; H. 4.40. CI. 9.81. N. 7.76; S. 9.06.

14 EXAMPLE 3 7-chloro-5-(o-chlorophenyl )-2.3-dihydro-2-thioxo-l H- 1,4-benzodiazepine-l-acetie acid methyl ester (V) A mixture of 3.8 g. (0.01 mole) of 7 ehloro-5-(ochlorophcnyl)-2,3-dihydro-2-oxo-1H-l ,4- benzodiazepine-l-acetic acid methyl ester (IV), 2.3 g. (0.0105 mole) of phosphorus pentasulfide and ml. of pyridine is heated under reflux for about 22 hours. The reaction mixture is evaporated and the residue thus obtained is dissolved in chloroform and 100 ml. of aqueous sodium bicarbonate solution. The organic layer is separated. washed with three 50ml. portions of aqueous sodium bicarbonate solution and with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The resi due (4.1 g.) thus obtained is dissolved in about 20 ml. of methylene chloride and chromatographed on 410 g. of silica gel. Elution with 50% ethyl acetate-methylene chloride gives 1.79 g. of 7-chloro-5-(o-ehlorophenyl)- 2,3-dihydro-2-thioxo-1H-1,4-benzodiazepine-1-acetic acid methyl ester. Recrystallization from ether gives 7- chloro-5-(o-chlorophenyl)-2.3-dihydro-2-thioxo-1H- 1,4-benzodiazepine-l-acetic acid methyl ester (V). m.p. 19l-192 C.; a sample recrystallized from methanol melts at 193-194 C.

Anal. Calcd. for C H C1 N O S: C, 54.97; H. 3.59; Cl, 18.03; N, 7.12; S. 8.15. Found: C. 54.82; H, 3.71; Cl. 18.15; N, 6.91; S. 8.37.

EXAMPLE 4 5-(o-chlorophenyl)2.3dihydro-2-thioxo-1H-1,4- benzodiazepine-l-aeetic acid methyl ester (V) A mixture of 7.75 g. (0.0226 mole) of 5-(0- chlorophcnyl)-2.3-dihydro-2-oxo-1H-1,4- benzodiazepine-l-aeetic acid methyl ester (IV). 5.3 g. (0.0238 mole) of phosphorus pentasulfide and 200 ml. of pyridine is heated under reflux for about 23 hours. The reaction mixture is then evaporated and the residue thus obtained is dissolved in methylene chloridewater. The organic layer is separated. washed with five 100-ml. portions of saturated aqueous sodium bicarbonate solution. dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue (7.3 g.) thus obtained is dissolved in 50 ml. of methylene chloride and ehromatographed on 730 g. of silica gel. Elution with 60% ethyl acetate-cyclohexane gives 4.8 g. of product which is triturated with methanol, fil' tered and washed with ether to give 3.5 g. of S-(ochlorophcnyl )-2.3-dihydro-2thioxol H-1 ,4- benzodiazcpine-l-acetic acid methyl ester (V); a sample after recrystallization from methanol-chloroform melts at 183184 C.

Anal. Calcd. for C ,,H ClN O S: C, 60.24; H. 4.21; C], 9.88; N. 7.81 S, 8.94. Found: C. 60.1 1; H. 4.20;Cl. 10.06; N. 7.39; S. 9.06.

EXAMPLE 5 7-chloro-5-( 2,6-difluorophenyl )-2.3-dihydro-otmethyl-Z-thioxo-l H-l ,4-benzodiazepine-1-acetic acid methyl ester (V) A mixture of 0.01 mole of 7-chloro-5-(2,6- difluorophenyl)-2,3-dihydro-a-methyl-Z-oxo-1H-1.4- benzodiaZcpin-l-acctic acid methyl ester (IV). 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyri dine is heated under reflux for about 24 hours. The reaction mixture is evaporated and the residue thus ob- 15 tained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent.

thioxo-lH-l,4-benzodiazepine-l-acetic acid methyl ester (V) A mixture of 0.01 mole of 7-chloro-5cyclohexyl-2.3-

The residue thus obtained is chromatographed on silica 5 dihydro-a'isopropyl'z'oxo'lH'l '4'benzodlazepine'l gel and eluted to give 7chloro-5-(2.6-difluorophenyl)- 2,3-dihydro-a-methyl-2-thioxo-lH-l.4- benzodiazepine-l-acetie acid methyl ester (V).

EXAMPLE 6 2,3-dihydro-5phenyl-2 thioxo-7-( trifluoromethyl lH-l,4-benzodiazepinc-l-acetic acid ethyl ester (V) A mixture of 0.0l mole of 7-trifluoromethyl-2,3- dihyd ro-2-oxo-5-phenyll H-l ,4-benzodiazepinl acetic acid ethyl ester (IV) and 0.0105 mole of phosphorus pentasulfide and I ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution. dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 2.3-dihydro--phenyl-2-thioxo-7- (trifluoromethyl l H- l .4-benzodiazepinel acetic acid ester (V).

EXAMPLE 8 7-ch1oro-a-ethyl-2,3-dihydro-a-methyl-2-thioxo-5-(ochlorophenyl l H- l .4-benzodiazepine-l -acetic acid propyl ester (V) A mixture of 0.0l mole of 7-chloro-a-ethyl-2.3- dihydro-a-methyl-2-oxo-5-( o-chlorophenyl l H-1 .4- benzodiazepine- 1 -acetic acid propyl ester (lV). 0.0105 mole of phosphorus pentasulfide and I00 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution. dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-chloro-a-ethyl-2.3-dihydro-a-methyl- 2-thioxo-5-(o-chlorophenyl )-l H- l .4-benzodiazepinel-acetic acid propyl ester (V) EXAMPLE 9 7-bromo-2 .B-dihydro-a-propyLS-t 2-pyridyl )-2-thioxolH-l .4-bcnzodiazepine-l-acetic acid methyl ester (V) A mixture of 0.0l mole of 7-bromo-2.3-dihydro-apropyl-5-( Z-pyridyl )-l H-l ,4-benzodiazepinel -acetic acid methyl ester (lV). 0.0105 mole of phosphorus pentasulfidc and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated. washed with saturated sodium bicarbonate solution. dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-bromo- 2.3-dihydro-a-propyl-5-(2-pyridyl )-2-thioxol H-l .4- benzodiazepine-l -acetic acid methyl ester (V).

EXAMPLE I0 7-chloro-5-cyclohexyl-2.3-dihydrou-isopropyl-Z- acetic acid methyl ester (IV), 0.0105 mole of phosphorus pentasulfide and I00 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated. washed with saturated sodium bicarbonate solution. dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-chloro- 5-cyclohexyl-2.3-dihydro-a-isopropyl-2-thioxol H- l,4-benzodiazepine-l-acetic acid methyl ester (V).

In the manner given in Examples l-IO. above, other 2,3-dihydro-2-oxol H- I .4-benzodiazepinel -acetic acid alkyl esters of formula IV. for example those prepared and listed in Preparation 9 above are reacted with phosphorus pentasulfide to obtain the correspond ing 2.3-dihydro-2-thioxol H-l .4-benzodiazepine-l acetic acid alkyl esters of formula V, such as:

7-bromo-2,3-dihydro-5-phenyl-2-thioxol H-l .4- benzodiazepine-l-acetic acid methyl ester;

7-f'luoro-2.3-dihydro-5-phenyl-2-thioxol H-l .4- benzodiazepine-l-acetic acid methyl ester;

2,3-dihydro-7-nitro-5-phenyl-2-thioxo-l H- l ,4- benzodiazepine-l-acetic acid methyl ester;

7-cyano-2.3-dihydro-5-phenyl-2-thioxol H- l .4- benzodiazepine-l-acetic acid methyl ester;

5-(o-chlorophenyl)-2.3-dihydro-7-(methylthio)-2- thioxo-l H-l,4-benzodiazepine-l-acetic acid methyl es ter;

7-br'omo-5-(o-chlorophenyl)-2.3-dihydro-2-thioxol,4-benzodiazepine-l-acetic acid methyl ester;

5-( o-chlorophenyl )-7-fluoro-2,3-dihydro-2-thioxolH-l,4-benzodiazepine-l-acetic acid methyl ester;

5-(o-chlorophenyl)-2,3-dihydro-7-nitro-2-thioxolH-l.4-benzodiazepine-l-acetic acid methyl ester;

5-(o-chlorophenyl)-2,3-dihydro-2,3-dihydro-2- thioxo-7-(trifluoro-methyl l H-l .4-benzodiazepinel- 17 benzodiazepine-l-acetic acid methyl ester;

7-fluoro-2.3-dihydro-5-( 2-pyrrolyl)-2-thioxo- 1 H- 1.4-benzodiazepine-l-acetic acid methyl ester;

2.3-dihydro5-(Z-thienyl)-7-nitro-2-thioxo-lH-1,4- benzodiazepine-l-acetic acid methyl ester;

5-cyc1ohexyl-2,3-dihydro-2-thioxo-7- (trifluoromethyl)-lH-l ,4-benzodiazcpine-1-acetic acid methyl ester;

7-cyano-5-(1-cyclohexenyl)-2.3-dihydro-2-thioxo- 1H-l,4-benzodiazepine-1-acetic acid methyl ester and the like.

EXAMPLE ll 9-chloro-3.S-dihydro-7-phenyl-as-triazino-l4,3- a][ l .4]benzodiazepin-2( 1H )-one (13.)

A mixture of 0.5 g. (1.4 millimoles) of 7-ch1oro-2,3- dihydro-S-phenyl-Z-thioxo-1H-l,4-benzodiazepine-lacetic acid methyl ester (V), 70 mg. (1.4 millimoles) of hydrazine hydrate (V111) and 10 m1. of methanol is re fluxed for about 3.75 hours. The mixture is allowed to cool, and the crystalline precipitate which separates is collected on a filter; yield, 0.280 g. of 9-ch1oro-3,5- dihydro-7-phenyl-as-triazinol4,3- all 1 .4lbenzodiazepin-2( l H )-one 1a). m.p. 267-270 C.

Anal. Calcd. for C H ClN O: C. 62.87; H. 4.03; C1. 10.92; N, 17.25. Found: C. 62.60; H. 3.991Cl. 10.69; N. 17.10.

EXAMPLE l2 9-chloro-7-( o-chlorophenyl )-3,5-dihydro-ustriazino[4.3-al[1,4]benzodiazepin-2(1H)-one (la) A mixture of 1.06 g. (2.7 millimoles) of 7-chloro-5- (o-chlorophenyl )-2.3-dihydro-2.3-dihydro-2-thioxo- 1H-1.4-henzodiazepine-1-acetic acid methyl ester (V). 0.14 g. (2.7 millimoles) of hydrazine hydrate (V111) and ml. of methanol is refluxed for about 5 hours. The reaction mixture is then concentrated to about hall of its original volume and allowed to crystallize to give on filtration 0.81 g. of 9-chloro-7-(o-chlorophenyl)- 3.5-dihydro-as-triazino[4,3-a][ 1.4]benzodiazepin- 2(1H)-onc (1a). m.p. 232-233 C.

Anal. Calcd. for C H Cl N O: C. 56.84; H. 3.37; C1, 19.74; N. 15.60. Found: C. 56.45; H. 3.33; CI. 19.92; N, 15.59.

EXAMPLE l3 9-ehloro-7-(o-chlorophenyl )-3.5-dihydro-3-methy1-astriazinol4,3-a]l l.4lbenzodiazepin-2( 1H )-onc (1a) A mixture of 0.8 g. (2.03 millimoles) of 7-ehloro-5- (o-chlorophenyl )-2.3-dihydro-2thioxo- 1 H-1 ,4- benzodiazepine-l-acetic acid methyl ester (V). 94 mg. (2.03 millimoles) of methyl hydrazine (V111) and 20 m1. of methanol is heated under reflux for about 16 hours and then allowed to stand for 2 days. The mixture is evaporated and the residue is dissolved in 10 ml. of 50% ethyl acetate-cyclohexane and 3 ml. of methylene chloride and ehromatographed on 90 g. of silica gel. Elution with 5% methanol-ethyl acetate gives 0.441 g. of 9-ch1oro-7-(o-chlorophenyl)-3.5-dihydro-3-methylastriazino[4.3-al [1 .4lbenzodiazepin-2H H l-one (1a). Crystallization from ether afforded 0.255 g. of 9- chloro-7'( o-chlorophenyl )-3.5-dihydro-3-methyl-astriazino[4.3-a| [1.4lbenzodiazepin-211Hl-onella); m.p. 170171 c.

18 Anal. Calcd. for C H CI N O: C, 57.92; H. 3.78; C1. 19.00; N. 15.01. Found: C. 57.62; H, 3.87; C1. 18.79; N. 14.88.

EXAMPLE l4 7-(o-chlorophenyl )-3,S-dihydro-as-triazino-l4,3- a][1,4]benzodiazepin-2(H)-one (1a) A mixture of 1.5 g. (4.34 millimoles) chlorophenyl )-2,3-dihydro-2-thioxo-l H-l ,4- benzodiazepine-l-acetic acid methyl ester (V). 0.217 g. (4.34 millimoles) of hydrazine hydrate (V111) and 20 m1. of methanol is heated under reflux for about 18.5 hours. concentrated to about half volume and allowed to stand. A yield of 1.004 g. of crystalline 7-(o chlorophenyl)-3,5-dihydro-as-triazino-[4,3- a][1,4]benzodiazepin-2(lH)-one (1a), m.p. 194-l 96 C.. is obtained. Recrystallization from methanolmethylene chloride raises the m.p. 195-196.5 C.

Anal. Calcd. for C, H ClN O.H O: C. 59.56; H, 4.41;Cl, 10.34; N. 16.53. Found: C, 59.67; H, 4.58; Cl, 10.92; N, 16.64.

EXAMPLE l5 7-( o-chlorophenyl )-3 .5-dihydro-3-methyl-astriazinol4,3-a1{1,4]benzodiazepin-2(1H)-one (1a) A mixture of 1.55 g. (4.34 millimoles) of 7-(ochlorophenyl)-2.3-dihydro-2-thioxo-1H-1.4- benzodiazepine-l-acetic acid methyl ester (V). 0.199 g. (4.34 millimoles) of methylhydrazine (V111) and 20 ml. of methanol is heated under reflux for about 18.5 hours. The reaction mixture is allowed to crystallize to give 0.303 g. of unreacted starting material which separates and is removed by filtration. The filtrate is evaporated and the residue thus obtained is dissolved in about 5 ml. of methylene chloride and chromatographed on g. of silica gel. Elution with ethyl acetate gives 0.806 g. of 7-(o-chlorophenyl)-3,5-dihydro- 3-methy1-as-triazino[4,3-all 1,4 ]benzodiazepin- 2(lH)-one (121) as an oil; UV, IR and NMR (CDCl;,) spectra are in accord with the structure.

EXAMPLE l6 9-chloro-3,5-dihydro-3-methyl-7-phenyl-astriazino[4.3-a][ l ,4]benzodiazepin-2( 1H )-one (13) A mixture of 1.1 g. (3.08 millimoles) of 7-chloro-2,3- dihydro-S-phenyl-Z-thioxo-1H-1,4-benzodiazepine 1- acetic acid methyl ester (V). 0.142 g. (3.08 millimoles) of methylhydrazine (V111) and 20 m1. of methanol is heated under reflux for about 20 hours. The reaction mixture is evaporated and the residue thus obtained is chromatographed on 240 g. of silica gel. Elution with ethyl acetate gives 0.523 g. of 9-chloro-3.5-dihydro-3- methyl-7-phenyl-as-triazinol4,3- all 1 .4]bcnzodiazepin-2( 1 H)-one 1a). which is recrystallized from ether to give 0.477 g. of 9-ch1oro-3.5- dihydro-3-methyl-7-phenyl-as-triazino[4.3-

a][ 1.4]benzodiazepin-2( 1H)-one 1a) as colorless needles; m.p. -176 C.

EXAMPLE 17 9-chloro-7-( 2.6-difluorophenyl )-3-ethyl-3.5-dihydro- 1-mcthyl-as-triazino[4.3-0 1,4]-benzodiazepin- 2(lH)-one (1a) A mixture of 3.0 millimoles o1 a-methyl-7-chloro- 2.3-dihydro-5-(2.6-dil1uorophcnyl)-2-thioxo-1H-l.4-

ness, and the residue thus obtained is chromatographed 5 on silica gel and eluted therefrom to give 9-chloro-7 (2.6-difluorophenyl-3-ethyl-3,S-dihydro-l -methyl-astriazino[4.3-a][ l ,4]benzodiazepin-2( lH)-orie (la).

EXAMPLE 18 3.5-dihydro7-phenyl-3-propyl-9trifluoromethyl-astriazino[4.3-a][1,4lbenzodiazepin-2(1H)-one (la) A mixture of 3-millimoles of 2,3-dihydro-5-phenyl-2- thioxo-7-(trifluoromethyl )-l H- l ,4-benzdiazepinel acetic acid ethyl ester (V), 3.0 millimoles of propylhydrazine (Vlll) and 20 m1. of methanol is heated under reflux until the reaction is complete. The reaction mixture is then evaporated to dryness, and the residue thus obtained is chromatographed on silica gel and eluted therefrom to give 3,S-dihydro-7-phenyl-3-propyl-9- trifluoromethyl-as-triazino-l 4,3-all l ,4 lbenzodiazepin- 2( lH)-one (1a).

EXAMPLE l9 9-chloro-3 .5-dihydro-3-isopropyll ,1 -dimethyl-7- phcnyl-as-triazinol4.3-all1.4]-benzodiazepin- 2( lH)-one (la) A mixture of 3.0 millimoles of 7chloro-2.3-dihydroa,a-dimethyl-5-phenyl-2-thioxo-lH-1 4- benzodiazepinel -acetic acid methyl ester (V 3.0 millimoles of isopropylhydrazine (Vlll) and 20 mlv of methanol is heated under reflux until the reaction is complete. The reaction mixture is then evaporated to dryness. and the residue thus obtained is chromatographed on silica gel and eluted therefrom to give 9' chloro-3,S-dihydro-B-isopropyLl.l-dimethyl-7-phenyl as-triazino[4.3-a][ l .4]benzodiazepin-2( lH )-one (la).

EXAMPLE 20 9-chloro-7-(o-chlorophenyl )-l-ethyl-3,5-dihydro-l ,3- dimethyl-as-triazinol4,3-u][1 4]-benzodiazepin- 2( lH)-one (la) A mixture of 3.0 millimoles of 7-chloro-5(o chlorophenyl)-a-ethyl-2,3-dihydro-a-methyl-2-thioxolH-l.4-benzodiazepine-l-acetic acid propyl ester (V), 3.0 millimoles of methyl hydrazine (Vlll) and 20 ml. of methanol is heated under reflux until the reaction is complete. The solvent is then removed from the reaction mixture by evaporation and the residue thus obtained is chromatographed on silica gel and eluted therefrom to give 9-chloro-7-(o-chlorophenyl )-1-ethyl- 3,5-dihydrol ,3-dimethyl-as-triazino-[ 4,3- all 1 .4lbenzodiazepin-2( lH)-one (la).

EXAMPLE 2l 9-bromo-3-ethyl-3.S-dihydro-l-propyl-7-(2-pyridyl)- astriazino[4,3a][ l.4]benzodiazepin-2( 1H )one (la) A mixture of 3.0 millimoles of 7-bromo-2 3-dihydroa-propyl-5-(2pyridyl)-2-thioxo-1H-l .4- benzodiazcpine-l-acetic acid methyl ester V). 3.0 millimoles of ethyl hydrazine (Vlll) and 20 ml. of methanol is heated under reflux until the reaction is complete. The solvent is then removed from the reaction mixture by evaporation and the residue thus obtained is chromatographed on silica gel and eluted therefrom to give 9-bromo-3-cthyl-3.S-dihydrol propyl7-( 2- 20 pyridyl )-as-triazino[4.3-a]l l .4 lbenzodiazepim 2( l H)-one (la).

EXAMPLE 22 9-chloro-7-cyclohexyl-3,S-dihydrol -isopropyl-3- propyl-as-triazino[4.3a]l l .4 ]benzodiazepin- 2(1H)-onc (la) A mixture of 3.0 millimoles of 7-chloro-5-cyclohexyl- 2,3-dihydro-a-isopropyl-Z-thioxo-1H-l.4-

benzodiazepinel -acetic acid methyl ester (V l, 3.0 millimoles of propylhydrazine (Vlll) and 20 ml. of methanol is heated under reflux until the reaction is complete. The solvent is then removed from the reaction mixture by evaporation and the residue thus obtained is chromatographed on silica gel and eluted therefrom to give 9-chloro-7-cyclohexyl-3,S-dihydrol isopropyl-3- propyl-as-triazino[4.3a][ 1,4)bcnzodiazepin- 2( lH)-one (la) In the manner given in Examples 1 l22, above, other 2,3-dihydro-2-thioxol H-l ,4-benzodiazepine- 1 -acetic acid alkyl esters of formula V, for example those prepared and listed in Example l0 above, are condensed with the appropriate hydrazine of formula Vlll to 0b- 25 tain other 3,5dihydro-as'triazino[4.3

a]a][1,4]benzodiazepin-2t lH)-ones of formula la; for

example reaction with hydrazine hydrate yields: 9bromo-3,5-dihydro-7-phenyl-as-triazino[4,3

all I .4 ]-benzodiazepin-2( l H )-one;

9fluoro-3,5-dihydro-7-phenyl-astriazinol4.3-

all l .4]-benzodiazepin-2( lH )-one;

3,S-dihydro-9-nitro-7-phenyl-as-triazino[4,3-

3.5-dihydro-7-phenyl-9-(trifluoromethyl)-as' triazino-[4,3-a][ l.4]bcnzodiazepin-2-( lH)-one;

9-cyano-3,5-dihydro-7-phenyl-as-triazinol4.3-

all l,4]-benzodiazepin-2( 1H )-one;

3,5-dihydro-9-methylthio)-7-phenyl-astriazinol4.3-

40 ai-l l ,4 ]benzodiazepin-2-( lH )-one;

9- bromo7-(o-ehlorophenyl )-3.5-dihydro-astriazino-[4.3-a][ l ,4lbenzodiazepin-2-( l H)-one;

7-( o-chlorophenyl )-9-fluoro-3,5-dihydro-as-triazino [4,3-a1l l ,4-]benzodiazepin-2( l H )-one; 7-(o-chlorophcnyl)-3.5-dihydro-9-nitro-as-triazino- [4.3-a][ l ,4 ]benzodiazepin-2( l H)-one;

7-(o-chlorophenyl)3.5dihydro-9trifluoromethyl) as-triazino[4,3-al[ l ,4 lbenzodiazepin-2( lH )-one;

7-( o-chlorophenyl )-9-cyano'3 .5-dihydro-as-triazinol4,3-a]l l ,4]benZodiazepin-2-( lH)-one;

7-(o-chlorophenyl)-3,5dihydro-9-(methylthio)-astriazino[4.3-a]l l ,4-lbenzodiazepin-2( lH)-one;

9-ehloro-7-(o-fluorophenyl)-3,S-dihydro-as-triazino- [4,3-all l ,4]benzodiazepin-2-( lH)-one; 9-bromo-7-(o-fluorophcnyl)-3.5-dihydro astriazino- [4.3-all l .4-lhenzodiazepin-2( l H)-one;

9-fluoro-7-(o-fluorophenyl)-3,S-dihydro-as-triazino- [4,3-all l ,4 |bcnzodiazepin-2( lH )-one;

7-( o-fluorophenyl )-3 ,5-dihydro-9-nitro-astriazino- [43a][ l .4]benzodiazepin 2( lH )-one;

7-(o-fluorophcnyl)3.5-dihydro-9-(trifluoromethyl)- as-triazinol4,3-a|[ l .4]bcnzodiazepin-2( lH)-one;

7-(o-chlorophenyl)-9-cyano-3,S-dihydro-as-triazino [4,3-ajl l,4]ben7.odiazepin-2( l H)-one;

7-(ofluorophenyl)-3,5-dihydro-9-(mcthylthio)-astriazino[4.3-a ll l.4]benzodiazepin-2( 1 H )-one;

9-chloro-3.5-dihydro-7-(Zpyrimidinyl)-as-triazino- (43-11 1 ,4]benzodiazepin-2( l H)one;

9bromo-7-(2-furyl)-3.S-dihydro-as-triazinol4.3-a]- [l.4]benzodiazepin-2( IH)-one;

3.5-dihydro-9-nitro-7-( 2-thienyl)-as-triazinol4.3-a]- I .4]benzodiazepin-2( IH)-one;

7-eyclohexyl-3.5-dihydro-9-(trifluoromethyl)-astriazino[4,3-a][ I.4-]benzodiazepin-2( lH)-one; and 9-cyano-7-( I-cyclohexenyl)'3.S-dihydro-as-triazino- [4.3-a][ I.4]benzodiazepin-2( l H)-one respectively, and the like.

In the same manner other alkylhydrazines of formula VIII, namely methylhydrazine.

ethylhydrazine.

propylhydrazine. and

isopropylhydrazine, can be substituted in place of hydrazine hydrate to obtain the corresponding 3-alkylsubstituted-3,5-dihydro-as-triazino[4.3- a][ I .4]benzodiazepin-2( lH)-ones of formula (Ia); e.g.. compounds corresponding to the compounds named hereinabove.

EXAMPLE 23 9'chIoro-3.5-dihydro-7-phenyl-as triazino-[4.3- a][ l.4]benzodiazepine-2( IH)-thione A mixture of 0.0l mole of 9-chIoro-3.5-dihydro-7- phenyl-as-triazinol 4.3-all 1.4Ibenzodiazepin- 2( IHIone. 0.0I05 mole of phosphorus pentasulfide and I ml. of pyridine is heated under reflux until the reaction is complete and then the solvent is removed by evaporation. The residue thus obtained is diluted with about I00 ml. of water and extracted with three I()()- ml. portions of methylene chloride. The methylene chloride extracts are combined. washed with aqueous sodium bicarbonate solution. then with aqueous satu rated salt solution and evaporated to remove the sol' vent. The residue thus obtained is redissolved in methylene chloride. chromatographed on silica gel and eluted to give 9-chloro3.5dihydro-7-phenyl-astriazino-[4.3- a][ I .4]benzodiazepine-2( 1H )-thione.

In the same manner following the procedures of Example 23. other 3.S-dihydro-as-triazinol4.3- a][l.4]benzodiazepin-2( IH)-ones of formula Ia are converted to the corresponding 3.5-dihydro-astria2ino[4.3u][ l.4jbcnzodiazcpine 2( IH )-thiones of formula lb; for example the compounds prepared in Examples I1-22. above. are converted to the corre sponding 2( lHl thiones (lb). The following conversions are representative:

9-chloro-7(o-chlorophenyl)-3.5-dihydro-astriazino-[4.3-a][l.4]benzodiazepin-2(lH)-one la) to 9-chloro-7-( o-chlorophenyl )-3.5-dihydro-astriazino[4.3-al[ l.4]-bcnzodiazepine-2( l H )-thionc lb);

9-ehloro-7-(o chlorophenyl)-3.5-dihydro-3-methylas-triazino[4.3 a]l l.4]benzodiazepin-2( IH )-one (Ia) to 9 chloro-7-(o-chlorophenyl)-3.5-dihydro-3-methyl as-triazino-l 4.3-a][ L4 Ibenzodiazepine2( l H )-thionc (lb);

7-(o-chlorophenyl)-3.5-dihydro-as-triazino[4.3- all I,4]-benzodiazepin-2( IH )-one (la) to chlorophenyl )3 .S-dihydro-as-triazinol 4.3

a][ I .4lbenzodiazcpine-2( IH)-thione (lb);

7-(o-chlorophenyl)-3.5-dihydro-3methyl-astriazino-l4.3-u]l l.4]benzodiazepin-2(lHl-one (Ia) to 7(o-chlorophenyl)3.5-dihydro-3-methyl-astriazino[4.3-a][ l.4]benzodiazepine-2( IH )-thione (l 9-chloro-3.S-dihydro-3-methyl-7-phenyI-as-triazino- [4.3-a][l.4]benzodiazepin-2(lH)-one (la) to 9- ehIoro-3.5-dihydro-3-methyl-7-phenyl-as-triazino[4.3- allI.4-]benzodiazepine-2(lH)-thione (lb); and the like.

EXAMPLE 24 9-chIoro-3,5-dihydro-7-phenyl-as-triazinol4,3- all I .4jbenzodiazepin-2( IH)-one 6-oxide (lc) A stirred solution of I .0 g. of 9-chloro-3,5-dihydro-7- phenyI-as-triazinol4.3-a]l1.4]benzodiazepin- 2( lH)-one (la) in absolute ethanol in an ice bath is treated with 1.0 g. of m-chloroperbenzoic acid. The mixture is allowed to stand in the ice bath for about 8 hours and at room temperature at about 24 C. for approximately I8 hours. It is then concentrated in vacuo and the residue thus obtained is suspended in cold, dilute aqueous potassium carbonate solution and ex tracted with methylene chloride. The extract is washed with water, dried and concentrated in vacuo. The residue thus obtained is chromatographcd on I00 g. of silica gel and eluted therefrom to give 9-chloro-3.5- dihydro-7-phenyl-as-triazino[4,3- a][I.4]benzodiazepin-2( IH)-one b-oxide (Ie).

EXAMPLE 25 9-ehloro-3,5-dihydro-7-phenyl-as-triazino-l4.3- a][ I,4]benzodiazepine-2( lH )-thione 6-oxide A stirred mixture of 1.0 g. of 9-chloro-3.S-dihydro7- phenyI as-triazino[4.3-a I ,4 ]benzodiazepine-2( l H thione la) in absolute ethanol in an ice bath is treated with LC g. of m-chloroperbenzoic acid. The mixture is allowed to stand in the ice bath for about 8 hours and at room temperature at about 24 C. for approximately I8 hours. It is then concentrated in vacuo and the residue thus obtained is suspended in cold. dilute aqueous potassium carbonate solution and extracted with methylene chloride. The extract is washed with water. dried and concentrated in vacuo. The residue thus obtained is chromatographed on I00 g. of silica gel and eluted therefrom to give 9-ehloro-3.5-dihydro-7-phenyI-astriazino[4,3-a][ I.4]benzodiazepine- 2( lH)-thione 6- oxide.

In the same manner following the procedure of Examples 24 and 25 above other 3.5-dihydro-astriazino[4.3-a][1.4J-benzodiazepin-2( IH)-ones of formula Ia and other 3.5-dihydro-as-triazino[4.3- a][l.4]benzodiazcpinc-2(lH)-thiones of formula lb. for example those compounds prepared in Examples 1 l-23 above, can likewise be converted to the corresponding o-oxides of formula Ie. The following conversions are representative:

9-chloro'7-(o-chlorophenyl)-3.5-dihydro-astriazino-[4.3-al[ l ,4]benzodiazepin-2( lH)-one (Ia) to 9-chloro-7'(o-ehlorophenyl)-3.5-dihydro-astriazino[4.3-al[ I.4]benzodia7.epin-2( I H)-one 6-oxide I lc);

9-chloro-7-(o-chlorophenyl)-3,5-dihydro-3-methylas-triazino[4.3-a]l I .4]benzodiazepin-2( lH)-one (la) to 9-ehloro-7-(o-chlorophenyl)-3.5-dihydro3-methyl as-triazino-l 4.3-all I .4]benzodiazepin-2( I H )-one 6- oxide (lc);

7-(o-ehlorophenyl)-3.5'dihydro-as-triazinol4,3-

all I.4]-benzodiazepin-2( l H)-one (Ia) to 7-(0- chlorophenyl )-3.5-dihydro-as-triazino[ 4.3-

23 a][ l .4]benzodiazepin2( 1H )-one fi-oxidc (lc);

7-(o-chlorophenyl)-3.5-dihydro-3-methyl-astriazino-[4.3-a][ l .4 ]benzodiazepin-2( lH)-one (la) to 7-(o-chlorophenyl)-3.5-dihydro-3-methyl-astriazino[4.3-a]-[ l.4]benzodiazepin-2( lH)-one 6-oxide (1c);

9-chloro-3,5-dihydro-3-mcthyl-7-phenyl-as-triazino- {4.3-a1ll.4]benzodiazepin-2(1H)-one (la) to 9- chloro-3.5-dihydro-3-methyl-7-phenyl-as-triazino[4.3- a][ l .4]benzodiazepin-2( I H)-one 6-oxide 9-ehloro-"l-(o-chlorophenyl)-3.5-dihydro-astriazino-l 4.3-a][ l.4]benzodiazepine-2( l H )-thione (lb) to 9-chloro-7-(o-chlorophenyl)-3.5-dihydro-astriazino[4.3-a][ l .4]bcnzodiazepine-2( lH )-thione 6- oxide (lc);

9-chloro-7-(o-chlorophenyl)-3,5-dihydro-3-methylas-triazino[4.3-a1[ l .4]benzodiazepine-2-( l H )-thione (lb) to 9-chloro-7-(o-chlorophenyl)-3.5-dihydro-3- methyl-as-triazino-[4,3-a][ l .4]benzodiazepine-2( l H thione -oxide;

7-(o-ehlorophenyl)-3.5-dihydro-as-triazino[4.3- alll.4]-benzodiazepine-2(lH)-thione (lb) to 7-(0- chlorophenyl )-3 ,5 dihydro-as-triazinol4.3- all I .4 ]benzodiazepine-2( l H )-thione o-oxide (lc 7-( o-chlorophenyl )-3 .5-dihydro-3-methyl-astriazino-[4.3-a][ 1.4 ]benzodiazepine-2( 1H )-thione (lb) to 7-(o-chlorophenyl)-3.5-dihydro-3-methyl-astriazinol 4.3-a][ 1.4 l-benzodiazepine-2( lH )-thione 6- oxide (lc):

9-chloro-3.5-dihydro-3-methyl-7-phenyl-as-triazino- [4.3-a1ll.4-benzodiazepinc-2(lH)-thione (lb) to 9- chloro-3.5-dihydro-3-methyl-7-phenyl-as-triazinol4.3- alll.4]-bcnzodiazcpinel2(lH)-thione 6-oxidc (Ic): and the like.

EXAMPLE 26.

9-chloro-3.5-dihydro-3-methyl-7-phenyl-astriazinol4.3-a][ l .4]benzodiazepin-2( lH l-one (la) To a solution of 9-chloro-3.5-dihydro-7-phenyl-astriazino[4.3-a][l.4benzodiazepin-2(lH) -one (la) in dimethylt'ormamide is added 1 molar equivalent of sodium hydride. The reaction mixture is stirred for about hours to complete the formation of the sodium salt. One molar equivalent of methyl iodide is then added and the reaction mixture is heated at about 95 c. until the reaction is complete. The solvent is then removed in vacuo and about 100 ml. of water is added. Extraction with methylene chloride and evaporation of the solvent gives 9-chloro-3.S-dihydro-3-methyl-7-phenylas-triazinol4.3-all l .4]-benzodiazepin-2( lH l-one (la).

Following the procedure of Example 26 other compounds of formula la, wherein R, is hydrogen. can be reacted with an alkyl halide to obtain the compounds of formula la wherein R is alkyl.

I claim:

I. A compound of the formula COORS wherein R and R. are each selected from the group consisting of hydrogen and alkyl of l to 3 carbon atoms. inclusive; R is selected from the group consisting of hydrogen. alkyl of l to 3 carbon atoms. inclusive. hydroxy, acetoxy and propionyloxy; R and R are each selected from the group consisting of hydrogen, alkyl of l to 3 carbon atoms, inclusive, halogen. nitro, cyano. amino. trifluoromethyl, alkoxy. alkylthio, alkylsulfinyl. alkylsulfonyl. alkanoylamino and dialkylamino in which the carbon chain moieties are of l to 3 carbon atoms. inclusive; R, is selected from the group consisting of pyridyl. Z-pyrimidinyl. furyl. pyrrolyl. thienyl, cycloalkyl of 5 to 7 carbon atoms. inclusive, cycloalkenyl of 5 to 7 carbon atoms, inclusive. and a phenyl radical of the formula in which R and R each have the same meanings as given above for R. and R and R is alkyl of l to 3 carbon atoms. inclusive.

2. 7-chloro-2.3-dihydro-5-phenyl-2-thioxo-l H-l .4- benzodiazepine-l-acetic acid methyl ester, the compound of claim I wherein R. R.. R and R are each hydrogen. R is 7-chloro. R is phenyl and R, is methyl.

3- 7-chloro-5-t o-chlorophenyl )-2 .3-dihydro-2- thioxo-lH-l.4-benzodiazcpine-l-acetic acid methyl ester. the compound of claim I wherein R. R R and s are each hydrogen. R is 7-chloro. R is o-chlorophenyl and R is methyl.

4. 5(0-chlorophenyl-2.3-dihydro-2-thioxo-l H-l .4- benzodiazepine-l-acetic acid methyl ester. the compound of claim I wherein R. R,. R R and R are each hydrogen. R is o-chlorophenyl and R is methyl. 

1. A COMPOUND OF THE FORMULA
 2. 7-chloro-2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepine-1-acetic acid methyl ester, the compound of claim 1 wherein R, R1, R3 and R5 are each hydrogen, R4 is 7-chloro, R6 is phenyl and R9 is methyl.
 3. 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepine-1 -acetic acid methyl ester, the compound of claim 1 wherein R, R1, R3, and R5 are each hydrogen, R4 is 7-chloro, R6 is o-chlorophenyl and R9 is methyl.
 4. 5(o-chlorophenyl-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepine-1-acetic acid methyl ester, the compound of claim 1 wherein R, R1, R3, R4 and R5 are each hydrogen, R6 is o-chlorophenyl and R9 is methyl. 